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RESEARCH PRODUCT
Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a target in LKB1 Mutant Lung Cancer
Zhao ChenKevin MarksQingsong LiuWilliam Y. KimLewis C. CantleyJohn V. HeymachNathanael S. GrayJeffrey A. EngelmanJohn M. AsaraNorman E. SharplessIgnacio I. WistubaLauren Averett ByersEdward M. DriggersRalph ScullyAbigail AltabefNirali M. PatelPeng GaoBrendan D. ManningDon L. GibbonsYan LiuTravis J. CohoonD. Neil HayesSung ChoeJulian CarreteroAndrew L. KungThomas J.f. NielandJianming ZhangSean T. BaileyReuben J. ShawAlec C. KimmelmanXiaoxu WangDavid E. RootDavid J. KwiatkowskiJeremy H. TchaichaPasi A. JänneGlenn S. CowleyYong ZhangChunxiao XuNabeel BardeesyKwok-kin Wongsubject
DNA Replicationcongenital hereditary and neonatal diseases and abnormalitiesLung NeoplasmsMutantSTK11BiologyAMP-Activated Protein KinasesProtein Serine-Threonine Kinasesmedicine.disease_causeArticleProto-Oncogene Proteins p21(ras)MiceDeoxythymidylate kinaseAMP-Activated Protein Kinase KinasesRNA interferenceCell Line TumorCarcinoma Non-Small-Cell LungmedicineMetabolomicsThymine NucleotidesAnimalsHumansMolecular Targeted TherapyLung cancerskin and connective tissue diseasesCell DeathModels GeneticKinaseCell growthGenomicsmedicine.diseaseMolecular biologyHigh-Throughput Screening AssaysOncologyGene Knockdown TechniquesCancer researchRNA InterferenceKRASNucleoside-Phosphate KinaseDNA Damagedescription
Abstract The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non–small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to define novel therapeutic targets in KRAS-driven LKB1-mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling showed that Lkb1-null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1–wild-type cells. Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors. Significance: Using cell lines derived from the lung cancers occurring in genetically engineered mice, we conducted an integrative genome-wide short hairpin RNA and metabolite screen to identify DTYMK as a potential therapeutic target in Kras/Lkb1–mutant lung cancer. We believe that DTYMK is tractable for the development of novel therapeutics, and show an integrative approach to target identification that reduces false-positive candidates and should have broad applicability for the development of targeted therapeutics. Cancer Discov; 3(8); 870–9. ©2013 AACR. See related commentary by Marcus and Khuri, p. 843 This article is highlighted in the In This Issue feature, p. 826
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2013-08-01 |